Respiratory pattern generation and motor output integration are strongly influenced by behavioral state. In extreme cases, the respiratory dysrhythmia permitted or provoked during rapid eye movement (REM) sleep appears to be a pathogenic factor for sleep-related breathing disorders such as sleep apnea syndrome. The neuronal networks and synaptic mechanisms that render autonomic outputs more labile during REM sleep remain poorly defined, but during the previous funding cycle we developed key evidence supporting a respiratory modulating function of the pedunculopontine tegmental (PPT) nucleus - an important region for REM sleep homeostasis and sensorimotor integration. Specifically, PPT stimulation produced respiratory dysrhythmia in sleeping and anesthetized animals and PPT lesions reduced apnea expression during REM sleep. Within the PPT, serotonin blunted glutamate-induced respiratory perturbation. Narcolepsy results from a loss of hypothalamic orexinergic neurons that provide excitatory inputs to PPT as well as to brainstem serotonergic neurons. REM sleep control is aberrant in narcolepsy and PPT dysfunction has been implicated. Moreover, the prevalence of sleep apnea is greatly increased among patients with narcolepsy. During years 11 to 13 of this program, we will pursue 3 specific aims to establish the importance of orexinergic modulation of respiratory integration, and the state-dependent role of the PPT in these effects. Aim 1 will quantify impairments to: respiratory chemoreflexes, respiratory short term potentiation (STP) and respiratory long term facilitation (LTF) during wakfulness and sleep in animals that spontaneously exhibit apnea during sleep;and will quantify the impact of orexin signaling on chemoreflexes, STP, LTF and apnea frequency. Aim 2 parallels an experiment of nature (narcolepsy), using pharmacologic blockade of orexin receptors and paired-pulse acoustic stimulation in conscious rats to determine if PPT-mediated gating of autonomic responses is impaired in the absence of orexin signaling. Aim 3 will further probe the specific role of the PPT in orexinergic regulation of respiratory, cardiovascular and skeletal motor outputs in anesthetized rats using a combination of systemic and local pharmacological manipulations of orexin activity. Similar targeted manipulations will be conducted in the raphe nuclei, an important source of serotonergic inputs to PPT. By extending the progress of the previous funding cycle, these aims will provide important insights regarding the state-dependent mechanisms by which the PPT modulates respiratory pattern in health and disease. PUBLIC HEALTH RELEVANCE: The proposed studies will test hypotheses related to the causes and consequences of sleep-related breathing disorders using a validated animal model system. Better understanding the mechanisms leading to apnea is of public health importance because sleep apnea syndrome is a common disorder that causes significant medical and behavioral morbidity and for which we do not have specific and fully acceptable treatments.